Method of controlling male fertility

ABSTRACT

A method of controlling male fertility in warm-blooded male animals comprising administering to male warm-blooded animals an amount of a compound selected from the group consisting of a compound of the formula ##STR1## wherein R 1  and R 2  are taken together with the nitrogen to form a saturated 5 to 6 ring heterocycle, optionally containing a second nitrogen or oxygen in the ring, R 3  is α- or β-methyl, n is an integer from 2 to 10, R 4  and R 5  together are ═0 or R 4  is selected from the group consisting of hydrogen, --OH and acyloxy of an organic carboxylic acid of up to 12 carbon atoms and R 5  is selected from the group consisting of hydrogen, --OH, acyloxy of an organic carboxylic acid of up to 12 carbon atoms and alkyl, alkenyl and alkynyl of up to 8 carbon atoms, R 6  and R 7  together are ═0 or are individually selected from the group consisting of hydrogen, --OH and acyloxy of an organic carboxylic acid of up to 12 carbon atoms or R 5  and R 6  form a double bond and R 4  and R 7  are hydrogen and their non-toxic, pharmaceutically, acceptable acid addition salts in an amount sufficient to control male fertility.

PRIOR APPLICATION

This application is a division of U.S. patent application Ser. No.401,078 filed Mar. 8, 1995 now U.S. Pat. No. 5,554,604.

STATE OF THE ART

The compounds of formula I are known to possess antilipemic orhypocholesterolamic properties.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a novel method ofcontrolling fertility in male warm-blooded animals.

This and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel method of the invention of controlling male fertility inwarm-blooded male animals comprises administering to male warm-bloodedanimals an amount of a compound selected from the group consisting of acompound of the formula ##STR2## wherein R₁ and R₂ are individuallyselected from the group consisting of alkyl of 1 to 8 carbon atoms andbenzyl or taken together with the nitrogen form a saturated 5 to 6 ringheterocycle optionally containing a second nitrogen or oxygen in thering, R₃ is α- or β-methyl, n is an integer from 2 to 10, R₄ and R₅together are ═O or R₄ is selected from the group consisting of hydrogen,═OH and acyloxy of an organic carboxylic acid of up to 12 carbon atomsand R₅ is selected from the group consisting of hydrogen, --OH, acyloxyof an organic carboxylic acid of up to 12 carbon atoms and alkyl,alkenyl and alkynyl of up to 8 carbon atoms, R₆ and R₇ together are ═Oor are individually selected from the group consisting of hydrogen, --OHand acyloxy of an organic carboxylic acid of up to 12 carbon atoms or R₅and R₆ form a double bond and R₄ and R₇ are hydrogen and theirnon-toxic, pharmaceutically acceptable acid addition salts in an amountsufficient to control male fertility.

Examples of R₁, R₂ and R₅ as alkyl of 1 to 8 carbon atoms includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl,n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl,2,2-dimethyl-pentyl, 3,3-dimethyl-pentyl, 3-ethylpentyl, n-octyl,2,2-dimethylhexyl, 3,3-dimethylhexyl and 3-methyl-3-ethylpentyl,preferably methyl, ethyl and isopropyl.

When R₁ and R₂ form with the nitrogen to which they are linked asaturated heterocycle with 5 or 6 members optionally containing anotherheteroatom chosen from oxygen and nitrogen, it is preferably piperidino,morpholino, piperazino or pyrrolidino.

Examples of acyloxy of an organic carboxylic acid of up to 12 carbonatoms acetyloxy, propionyloxy, butyryloxy, hexanoyloxy and benzoyloxy.Formyloxy can also be mentioned.

Examples of alkenyl having at most 8 carbon atoms are vinyl, allyl,1-propenyl, butenyl, pentenyl or hexenyl and examples of alkynyl havingat most 8 carbon atoms are ethynyl, propargyl, butynyl, pentynyl orhexynyl.

Examples of suitable acids for the non-toxic, pharmaceuticallyacceptable acid addition salts are hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid,propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid,tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid,alkane sulfonic acids such as methane or ethane sulfonic acid,arylsulfonic acids such as benzene acid or p-toluene sulfonic acid andarylcarboxylic acids. Hydrochloric acid salts are preferred.

The wavy lines in positions 8, 9 and 14 indicate that the hydrogens arein position (8β,9α,14α) or (8α,9β,14β).

Among the preferred compounds of the invention are those wherein R₃ is aβ-methyl, those of the formulae ##STR3## wherein R₁ , R₂, R₅ and n aredefined as above, those of the formula ##STR4## wherein R₁ and R₂ areindividually alkyl of 1 to 8 carbon atoms, n is defined as above andeither R₄ is hydrogen and R₅ is --OH or R₄ and R₅ together are ═O or R₄and R₅ are both hydrogen, those of the formulae ##STR5## wherein R₁, R₂and n are defined as above and either R₄ and R₅ together are ═O or areindividually selected from the group consisting of hydrogen, --OH andacyloxy of an organic carboxylic acid of up to 12 carbon atoms and R₆and R₇ together form ═O or are individually selected from the groupconsisting of hydrogen, --OH and acyloxy of an organic carboxylic acidof up to 12 carbon atoms or R₅ and R₆ form a double bond and R₄ and R₇are hydrogen and their non-toxic, pharmaceutically acceptable acidaddition salts.

More preferred compounds of formula I are those wherein R₁ and R₂ areboth methyl or ethyl, those wherein n is 2 and their acid additionsalts.

Specific preferred compounds of the invention are:

3- 2-(dimethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-17-one,

3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-17-one,

3- 2-(dimethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-17-onehydrochloride,

3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-17-one hydrochloride,

3- 2-(1-piperidinyl)-ethoxy!-Δ¹,3,5(10) -estratrien-17-one,

3- 2-(4-morpholinyl)-ethoxy!-Δ¹,3,5(10) -estratrien-17-one,

3- 3-(dimethylamino)-propoxy!-Δ¹,3,5(10) -estratrien-17-one,

3- 3-(diethylamino)-propoxy!-Δ¹,3,5(10) -estratrien-17-one,

3- 4-(dimethylamino)-butoxy!-Δ¹,3,5(10) -estratrien-17-one,

3- 5-(dimethylamino)-pentyloxy!-Δ¹,3,5 (10) -estratrien-17-one,

3- 5-(diethylamino)-pentyloxy!-Δ¹,3,5(10) -estratrien-17-one,

3- 10-(dimethylamino)-decyloxy!-Δ¹,3,5( 10)-estratrien-17-one,

3- 2- methyl-(benzyll)-amino!-ethoxy!-Δ¹,3,5(10) -estratrien-17-one,

3- 3- bis(benzyl)-amino!-propoxy-Δ¹,3,5(10) -estratrien-17-one,

(17β)-3- 2- methyl-(benzyl)-amino!-ethoxy!-Δ¹,3,5(10) -estratrien-17-ol,

(17β)-3- 3-(dimethylamino)-propoxy!-Δ¹,3,5(10) -estratrien-17-ol,

(17β)-3- 3-(diethylamino)-propoxy!-Δ¹,3,5(10) -estratrien-17-ol,

(17α)-3- 3-(diethylamino)-propoxy!-Δ¹,3,5(10) -estratrien-17-ol,

(17α)-3- 2-(dimethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-17-ol,

(17α)-3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-17-ol,

3- 2-(dimethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-16-one,

3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-16-one,

3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-16-one hydrochloride,

3- 2-(dimethylamino)-ethoxy!-Δ¹,3,5(10) -estratriene,

3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10) -estratriene,

3- 2-(1-piperidinyl)-ethoxy!-Δ¹,3,5(10) -estratriene,

3- 3-(1-piperidinyl)-propoxy!-Δ¹,3,5(10) -estratriene,

3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10) -estratriene hydrochloride,

3- 2-(4-morpholinyl)-ethoxy!-Δ¹,3,5(10) -estratriene,

3- 2-(dimethylamino)-ethoxy!-Δ¹,3,5(10),16 -estratetraene,

3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10),16 -estratetraene,

(17α)-3- 3-(dimethylamino)-propoxy!-17-methyl-Δ¹,3,5(10)-estratrien-17-ol,

(17α)-3- 2-(dimethylamino)-ethoxy!-17-methyl -Δ¹,3,5(10)-estratrien-17-ol,

(17α)-3- 3-(dimethylamino)-propoxy!-19-nor-Δ¹,3,5(10)-pregnatrien-17-ol,

(17α)-3- 2-(dimethylamino)-ethoxy!-19-nor-Δ¹,3,5(10) -pregnatrien-17-ol,

(17α)-3- 2- methyl(benzyl)-amino!-ethoxy!-19-nor-Δ¹,3,5(10)-pregnatrien-17-ol,

(17α)-3- 3-(dimethylamino)-propoxy!-17-propyl-Δ¹,3,5(10)-estratrien-17-ol,

(17α)-3- 3-(dimethylamino)-propoxy!-17-propyl-Δ¹,3,5(10)-estratrien-17-ol hydrochloride,

(17α)-3- 3-(dimethylamino)-propoxy!-17-(1-propenyl)-Δ¹,3,5(10)-estratrien-17-ol,

(17α)-3- 3-(dimethylamino)-propoxy!-17-(1-propenyl)-Δ¹,3,5(10)-estratrien-17-ol hydrochloride,

(17α)-3- 2-(dimethylamino)-ethoxy!-19-nor-Δ¹,3,5(10),20-pregnatetraen-17-ol,

(17α)-3- 3-(dimethylamino)-propoxy!-19-nor-Δ¹,3,5(10),20-pregnatetraen-17-ol,

(17α)-3- 2-(dimethylamino)-ethoxy!-19-nor-Δ¹,3,5(10)-pregnatrien-20-yn-17-ol,

(17α)-3- 3-(dimethylamino)-propoxy!-19-nor-Δ¹,3,5(10)-pregnatrien-20-yn-17-ol,

(17α)-3-3-(dimethylamino)-propoxy!-19-nor-Δ1,3,5(10)-pregnatrien-20-yn-17-olhydrochloride,

(17α)-3- 2-(diethylamino)-ethoxy!-19-nor-Δ¹,3,5(10)-pregnatrien-20-yn-17-ol,

(17α)-3- 3-(diethylamino)-propoxy!-19-norΔ¹,3,5(10)-pregnatrien-20-yn-17-ol,

(17α)-3- 2- methyl(benzyl)-amino!-ethoxy!-19-nor-Δ¹,3,5(10)-pregnatrien-20-yn-17-ol,

(17α)-3- 2- methyl(benzyl)-amino!-ethoxy!-19-nor-Δ¹,3,5(10)-pregnatrien-20-yn-17-ol hydrochloride,

(17α)-3- 3- methyl(benzyl)-amino!-propoxy!-19-nor-Δ¹,3,5(10)-pregnatrien-20-yn-17-ol,

(8α,9β,13α,14β)-3- 2-(dimethylamino)-ethoxy!-Δ.sup.1,3,5(10)-estratrien-17-one,

(8α,9β,13α,14β)-3- 2-(diethylamino)-ethoxy!-Δ.sup.1,3,5(10)-estratrien-17-one,

(8α,9β,13α,14β)-3- 2-(dimethylamino)-ethoxy!-Δ.sup.1,3,5(10)-estratriene,

(8α,9β,13α,14β)-3- 2-(diethylamino)-ethoxy!-Δ.sup.1,3,5(10)-estratriene,

(8α,9β,13α,14β)-3- 2-(diethylamino)-ethoxy!-Δ.sup.1,3,5(10) -estratrienehydrochloride,

(8α,9β,13α,14β,17α)-3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10)-estratrien-17-ol,

(13α)-3- 2-(dimethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-17-one,

(13α)-3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10) -estratrien-17-one,

(13α)-3- 2-(dimethylamino)-ethoxy!-Δ¹,3,5(10) -estratriene,

(13α)-3- 2-(diethylamino)-ethoxy!-Δ¹,3,5(10) -estratriene, and theirnon-toxic, pharmaceutically acceptable acid addition salts.

The compounds of formula I are known and can be prepared by theprocesses described in British patents No. 984,028 and No. 984,029, U.S.Pat. No. 3,212,971, French patent No. 1,338,308 and French patents ofaddition No. 90,803 and No. 90,804.

It has now been found that the compounds of formula I have usefulproperties in the regulation of calcium flow in the spermatozoid. Theproducts have 1) a strong affinity for the Sigma receptors (seepharmacological tests) and 2) an activity vis-a-vis the influx of thecalcium into the spermatozoid.

Results of tests show that among the products which fix to the Sigmareceptors, certain act by stimulating the influx of calcium into thespermatozoid, others by inhibiting the influx of calcium stimulated ornot by progesterone, a molecule described as binding to the Sigmareceptor. The products of formula I have an agonist activity andstimulate the influx of calcium into the spermatozoid. They cantherefore be used in the treatment of certain forms of sterilitycharacterized by an insufficient fertilizing power of the spermatozoids.

The products of formula I having an antagonist activity inhibit theinflux of calcium into the spermatozoid. They are therefore useful forcontrolling the acrosomial reaction and consequently affect thefertilizing power of the spermatozoid. They can therefore be used as acontraceptive and in particular as a male contraceptive. They can alsobe used in the veterinary field as a male contraceptive in domesticanimals (dogs, cats . . . ) or to limit the proliferation of any pests,in particular rodents or pigeons.

The useful dose varies as a function of the illness to be treated andthe administration route. It can vary for example from 0.1 to 13 mg/kgper day in an adult man by oral route.

The compounds of formula I can be administered orally, rectally,parenterally or by local route, particularly for a woman, for example bypercutaneous route, or by injection, in particular sub-cutaneous in theveterinary field.

They can be in the form of tablets, dragees, capsules, granules,suppositories, injectable preparations, pessaries, particularly vaginalpessaries and ointments, creams, gels, microspheres, implants andpatches prepared by the usual methods.

Examples of suitable excipients are talc, gum arabic, lactose, starch,magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fattysubstances of animal or vegetable origin, paraffin derivatives, glycols,various wetting, dispersing or emulsifying agents and preservatives.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

PHARMACOLOGICAL TESTS METHOD Preparation of the Human Spermatozoids

The human sperm originated from healthy donors. The mobile spermatozoidswere separated by centrifugation on a Percoll gradient (47.5-95%), thenresuspended in a hypertonic BWW medium containing: 166 mM of NaCl, 5 mMof KCl, 1.3 mM of CaCl₂, 1.2 mM of KH₂ PO₄, 1.2 mM of MgSO₄, 5.5 mM ofglucose, 21 mM of sodium lactate, 0.25 mM of sodium pyruvate, 25 mM ofNaHCO₃, 20 mM of Hepes and 0.8% of HSA (410 mosm/liter), pH 7.4 atambient temperature.

Measurement of the Intracellular Calcium

The mobile spermatozoids were incubated for a minimum of 2 hours in theBWW/HSA capacitating medium. They were then incubated at a concentrationof 5-10×10⁶ /ml with Fura2-AM (final concentration 2 μM) at 37° C. for45 minutes. After washing by centrifugation for 10 minutes in BWWwithout HSA, the spermatozoids were resuspended at a concentration of4×10⁶ /ml. The fluorescence signal was measured at 37° C. using aspectrofluorimeter at excitation wave lengths of 340 and 380 nm (PTIM2001-Kontron) or at 340, 360 and 380 nm (Hitachi F 2000-B. Braun ScienceTec.). The fluorescence emission was recorded at 505 nm. Theprogesterone or the product to be tested, dissolved in absolute ethanol,were added to the incubation medium at a final concentration of 0.1% ofethanol. When an antagonistic effect of the progesterone was found, theproduct was added to the medium 2 minutes before the progesterone. Atthe end of the each dosage, 5 μM of ionomycin were added to the sampleto measure the maximum fluorescence signal. Then, the spermatozoids werepermeabilized with 0.05% of Triton X-100 and 10 mM of EGTA were added(pH 9.5) to measure the minimum fluorescence signal. These valuesallowed the intracellular concentration of calcium ( Ca²⁺ !i) to becalculated by the method described by Grunkiewicz et al, (1985) J. Biol.Chem., Vol. 260, pp. 3440-3450. The results of the intracellular calciumconcentrations were expressed relative to the basal level which wasarbitrarily set to equal to 1.

Sigma Receptor: Measurement of the Relative Bond Affinity

The relative bond affinity was evaluated for preparations of rat brainand testicle membranes.

Preparation of the membranes:

Male Sprague-Dawley rats originating from Iffa Credo and weighingapproximately 200 g were used. The animals were sacrificed bydecapitation and the brain and testicles were removed and homogenized in10 to 25 volumes of 50 mM Tris-HCl buffer (pH 7.7) at 4° C., using anUltrathurax. The homogenates were centrifuged at 30,000 g for 15 minutesat 4° C. The pellets were then washed 3 times by resuspension in thesame buffer and centrifugation under the same conditions. The membranesobtained in this way were stored at -80° C.

Incubation:

The marker of the sigma receptors used was ³ H PPP(propyl-3-(3-hydroxyphenyl)-piperidine) of NEN having a specificactivity of 3404 GBq/mmol. The membranes were resuspended in 50 mM ofTris-HCl buffer, pH 8.0 to obtain a concentration of proteins ofapproximately 0.6 mg/ml for the testicles and 1 mg/ml for the brain.Aliquots of the homogenate were incubated for 90 minutes at 25° C. in atotal volume of 0.5 ml with 3 nM of ³ H PPP in the presence ofincreasing concentrations of reference product (haloperidol) or of theproducts to be tested. At the end of the incubation, the ³ H PPP boundto the membranes was separated from the free ³ H PPP by rapid filtrationon Whatman GF/C filters pre-treated beforehand with 0.05% ofpolyethyleneimine. The precipitate was washed twice with 5 ml ofTris-HCl buffer and counting of the radioactivity was carried out afterthe addition of 20 ml of scintillating liquid Aqualyte (Baker).

Calculation of the relative bond affinity (RBA):

The following two curves were drawn: percentage of bound tritiatedmarker 100×B/BO as a function of the logarithm of the concentration ofunlabelled reference product or as a function of the logarithm of theconcentration of unlabelled test product. The straight line of thefollowing equation was determined:

    I.sub.50 =100 (BO/BO+Bmin/BO)/2 i.e.

    I.sub.50 =100 (1+Bmin/BO)/2=50(1+Bmin/BO)

BO=concentration of the bound tritiated marker in the absence of anyunlabelled product.

B=concentration of the bound tritiated marker in the presence of aconcentration X of unlabelled product.

Bmin=concentration of the bound tritiated marker in the presence of alarge excess of the unlabelled reference product (5,000 nM).

The intersections of the straight line I₅₀ and the curves allowed theevaluation of the concentrations of the unlabelled reference product(CH) and of the unlabelled test product (CX) which inhibited by 50% thespecific binding of the tritiated marker of the receptor. The relativebond affinity (RBA) of the test product was determined by the equation:

    RBA=100 (CH)/(CX).

The RBA of the haloperidol was arbitrarily set equal to 100.

    ______________________________________                                        Relative bond affinity for the Sigma receptor                                                      Brain  Testicle                                          Products             (rat)  (rat)                                             ______________________________________                                        Haloperidol          100.0  100.0                                             Progesterone         0.7    0.3                                               Estrone              <0.06                                                    (8α,9β,13α,14β)-3- 2-                                                        23.0   0.5                                               (dimethylamino)-ethoxy-                                                       .increment..sup.1,3,5(10) -estratriene                                        (product X)                                                                   3- 2-(diethylamino)- 85.0   12.5                                              ethoxy-.increment..sup.1,3,5(10) -estra-                                      trien-17-one (product W)                                                      3- 2-(1-piperidinyl)-ethoxy!-                                                                      28.0                                                     .increment..sup.1,3,5(10) -estratrien-17-                                     one                                                                           (13α)-3- 2-diethylamino)-                                                                    39.0                                                     ethoxy!-.increment..sup.1,3,5(10) -estra-                                     trien-17-one                                                                  3- 2-(1-piperidinyl)-ethoxy!-                                                                      54.0                                                     .increment..sup.1,3,5(10) -estratriene                                        (8α,9β,13α,14β)-3- 2-(diethyl-                                               28.0                                                     amino) -ethoxy-.increment..sup.1,3,5(10) -estra-                              triene hydrochloride                                                          (17α)-3- 2-(diethylamino)-                                                                   24.0                                                     ethoxy!-19-nor-.increment..sup.1,3,5(10) -                                    pregnatrien-20-yn-17-ol                                                       ______________________________________                                    

    ______________________________________                                        Increase in the concentration of intracellular calcium                        ( Ca.sup.2+ !i) induced by progesterone and product W                                     Progesterone                                                                          Product W                                                             (10.sup.-5 M)                                                                         (10.sup.-5 M)                                             ______________________________________                                        Exp. 1        4.25      3.56                                                  Exp. 2        6.60      2.55                                                  ______________________________________                                    

These results were expressed relative to the basal level set equal to 1.

The initial base levels were Exp. 1=200 nm and Exp. 2=250 nm.

    ______________________________________                                        Effective dose of product X on ( Ca.sup.2+ !i)                                PRODUCT X                                                                     10.sup.-7 M                                                                              10.sup.-6 M                                                                           5 × 10.sup.-6 M                                                                    10.sup.-5 M                                                                         2 × 10.sup.-5                       ______________________________________                                                                            M                                         Exp. 1                                                                              1.50     1.63    2.55     7.20  8.50                                    Exp. 2                                                                              1.38     1.78    5.56     12.00 8.00                                    ______________________________________                                    

The results were expressed relative to the basal level set equal to 1.

    ______________________________________                                        Comparison of effects of progesterone at 10.sup.-5 and product × at     10.sup.-5                                                                     M on  Ca.sup.2+ !i Mean ± SEM n = 3                                        Progesterone  Product X                                                       ______________________________________                                        4.90 ± 0.92                                                                              4.80 ± 0.92                                                  ______________________________________                                    

The results were expressed relative to the basal level set equal to 1.

CONCLUSION Effect on the Intracellular Calcium of Human Spermatozoids

Progesterone at the concentration of 10⁻⁵ M induced a transitoryincrease of the Ca²⁺ !i followed by a second phase where the Ca²⁺ !i wasslightly greater than the basal level.

Product X caused a dose-dependent increase of the Ca²⁺ !i which at 10⁻⁵M reached an intensity equal to that caused by progesterone. Contrary towhat was observed with progesterone, this effect was prolonged overtime.

Relative Bond Affinity (RBA) for the Sigma Receptor

The product X and progesterone were capable of displacing ³ H PPP. TheRBA's calculated using rat brain membranes have also been evaluated ontesticles and are given in the table.

The differences observed between the RBA's at the level of the brain andtesticles could be explained by a different distribution of the varioustypes of sigma receptor sites between these two organs. Such productscan therefore stimulate the acrosomial reaction in the case of theagonists such as product X and can therefore be used in certain forms ofsterility characterized by an insufficient fertilizing power of thespermatozoids.

Various modifications of the method of the invention may be made withoutdeparting from the spirit or scope thereof and it is to be understoodthat the invention is intended to be limited only as defined in theappended claims.

What we claim is:
 1. A method of controlling male fertility inwarm-blooded animals comprising orally administering to malewarm-blooded animals an amount of a compound selected from the groupconsisting of a compound of the formula ##STR6## wherein R₁ and R₂ takentogether with the nitrogen form a saturated 5 to 6 ring heterocycleoptionally containing a second nitrogen or oxygen in the ring, R₃ is α-or β-methyl, n is an integer from 2 to 10, R₄ and R₅ together are ═O orR₄ is selected from the group consisting of hydrogen, --OH and acyloxyof an organic carboxylic acid of up to 12 carbon atoms and R₅ isselected from the group consisting of hydrogen, --OH, acyloxy of anorganic carboxylic acid of up to 12 carbon atoms and alkyl, alkenyl andalkynyl of up to 8 carbon atoms, R₆ and R₇ together are ═O or areindividually selected from the group consisting of hydrogen, --OH andacyloxy of an organic carboxylic acid of up to 12 carbon atoms or R₅ andR₆ form a double bond and R₄ and R₇ are hydrogen and their non-toxic,pharmaceutically acceptable acid addition salts in an amount sufficientto control male fertility by affecting the fertilizing power of thespermatozoids without hormonal activity.
 2. The method of claim 1wherein the compound is selected from the group consisting of a compoundof the formula ##STR7## wherein the substituents are defined as in claim1 and their non-toxic, pharmaceutically acceptable acid addition salts.3. The method of claim 1 wherein the compound is selected from the groupconsisting of a compound of the formula ##STR8## wherein R₁, R₂, R₅ andn have the definitions of claim 1 and their non-toxic, pharmaceuticallyacceptable acid addition salts.
 4. The method of claim 1 wherein thecompound is selected from the group consisting of a compound of theformula ##STR9## wherein R₁, R₂ are defined as in claim 1 and theirnon-toxic, pharmaceutically acceptable acid addition salts.
 5. Themethod of claim 1 wherein the compound is selected from the groupconsisting of a compound of the formula ##STR10## wherein R₁ , R₂ and nare defined as in claim 1 and their non-toxic, pharmaceuticallyacceptable acid addition salts.
 6. The method of claim 1 wherein thecompound is selected from the group consisting of a compound of theformula ##STR11## wherein R₁, R₂ and n are defined as in claim 1 andeither R₄ and R₅ together are ═O or are individually selected from thegroup consisting of hydrogen, --OH and acyloxy of an organic carboxylicacid of up to 12 carbon atoms, R₆ and R₇ together are ═O or areindividually selected from the group consisting of hydrogen, --OH andacyloxy of an organic carboxylic acid of up to 12 carbon atoms, or R₅and R₆ form a double bond and R₄ and R₇ are hydrogen and theirnon-toxic, pharmaceutically acceptable acid addition salts.
 7. Themethod of claim 1 wherein n is
 2. 8. The method of claim 1 wherein thecompound is selected from the group consisting of3-2-(1-piperidinyl)-ethoxy!-Δ¹,3,5(10) -estratriene-17-one, 3-2-(4-morpholinyl)-ethoxy!-Δ¹,3,5(10) -estratriene-17-one, 3-2-(1-piperidinyl)-ethoxy!-Δ¹,3,5(10) -estratriene, 3-2-(4-morpholinyl)-ethoxy!-Δ¹,3,5(10) -estratriene, 3-3-(1-piperidinyl)-propoxy-Δ¹,3,5(10) -estratriene,and their non-toxic,pharmaceutically acceptable acid addition salts.